Ammonia → Dimiracetam

Temperature

65 °C

A suspension of 90.0 g (0.798 mol) of glycinamide hydrochloride (purity 98%) in 7.2 liter of n-propanol is heated to reflux, and 250 ml of solvent are distilled off. A 15% w/v solution of sodium tert-butoxide in n-propanol (260 ml, 0.35 mol) are added and an apparent pH of 5.5 is measured. Maintaining this apparent pH at 5.5 by automatic addition of a 15% w/v solution of sodium tert-butoxide in n-propanol, ethyl 4-oxobutanoate (purity 97%) (262.3 g, 1.955 mol) is added dropwise during four hours while keeping the reaction mixture at reflux, continuously distilling the solvent at about 400 ml/h and continuously adding n-propanol to the reaction mixture at about 400 ml/h. A total amount of 363 ml (0.476 mol) of sodium tert-butoxide 15% w/w solution in n-propanol is added. The mixture is stirred at reflux for additional 1.5 hours and then cooled to 65° C. A 7.5% w/w solution of ammonia in n-propanol (800 g) is slowly added to the mixture during 6 hours, and heating at 65° C. is continued for additional 18 hours. The reaction mixture is cooled to room temperature and the precipitate is filtered off. The clear solution is concentrated to a small volume (about 0.5 liter) under vacuum and stirred at 0° C. for 2 hours. The white precipitate is collected by suction filtration, washed with 50 ml of n-propanol and dried under vacuum at 60° C. for 12 hours to afford pure dimiracetam (65 g, 58.1%), melting at 154° C. HPLC purity: 99.7%

1. temperatureis heated
2. temperatureto reflux
3. distillation250 ml of solvent are distilled off
4. additionare added
5. temperatureMaintaining this apparent pH at 5.5
6. additionis added dropwise during four hours
7. temperatureat reflux
8. distillationcontinuously distilling the solvent at about 400 ml/h and continuously adding n-propanol to the reaction mixture at about 400 ml/h
9. temperatureat reflux for additional 1.5 hours
10. temperatureheating at 65° C.
11. temperatureThe reaction mixture is cooled to room temperature
12. filtrationthe precipitate is filtered off
13. concentrationThe clear solution is concentrated to a small volume (about 0.5 liter) under vacuum
14. stirringstirred at 0° C. for 2 hours
15. filtrationThe white precipitate is collected by suction filtration
16. washwashed with 50 ml of n-propanol
17. customdried under vacuum at 60° C. for 12 hours

ORD record

ord-860014fc42e44752a715258ffa68bab4

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08476453B2